This application is a National Stage Application of International Application Number PCT/GB00/04865, filed Dec. 18, 2000 published, pursuant to PCT Article 21(2), in English.
This invention relates to hydroxamic acid derivatives, and to their use in medicine.
Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNFxcex1 from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-9603571 1, WO-A-96035712 and WO-A-96035714.
Further, somewhat related compounds are disclosed in U.S. Pat. No. 5,892,112, WO-A-9724117 and FR-A-2597865.
Compounds according to the invention are of formula (I): 
wherein
R1 is a group (optionally substituted with R3) selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl; and
R2 is H or C1-6 alkyl;
or CR1R2 is cycloalkyl or heterocycloalkyl optionally substituted with R3 or a group (optionally substituted with R3) selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl and C1-6 alkyl-heteroaryl;
R3 is OR7, COR7, CO2R6, CON(R7)2, N(R7)2, NR7COR7, NR7CON(R7)2, NR7CO2R8, NR7SO2R8, S(O)0-2R8 and SO2N(R7)2; or cycloimidyl (optionally substituted with R4)
R4 is C1-6 alkyl;
Bxe2x80x94Nxe2x80x94B is heterocycloalkyl optionally substituted with R5 or xe2x95x90NOR5;
R5 is H, R6 or a group (optionally substituted with R6) selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl;
R6 is H or a group selected from N(R7)2 NR7COR7, NR7CON(R7)2, NR7CO2R8, NR7SO2R8, OR7, COR7, CO2R4, CON(R7)2, S(O)0-2R8 and SO2N(R7)2;
R7 is H or a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, S(O)0-2R8, CO2R8, OR8, CONR4R8, NR6R8 or SO2NR4R8, and for each case of N(R7)2 the R7 groups are the same or different or N(R7)2 is heterocycloalkyl optionally substituted with R8, COR8, S(O)0-2R8, CO2R8, OR8, CONR4R8, NR6R8 or SO2NR4R8; and
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
Preferred compounds of the invention are those wherein R1 is C1-6 alkyl or CR1R2 is heterocycloalkyl.
The compounds of the Examples are particularly preferred.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof
It will further be appreciated that the compounds according to the invention may contain an oxime. This oxime can give rise to geometrical isomers, and in each case the invention is to be understood to extend to all such isomers and mixtures thereof As used in this specification, alone or in combination, the term xe2x80x9cC1-6alkylxe2x80x9d refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
The term xe2x80x9cC2-6 alkenylxe2x80x9d refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
The term xe2x80x9cC2-6 alkynylxe2x80x9d refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 1-methyl-2-butynyl etc.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term xe2x80x9ccycloalkenylxe2x80x9d refers to an alicyclic moiety having from three to six carbon atoms and having in addition one double bond. This term includes, for example, cyclopentenyl and cyclohexenyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a saturated heterocyclic moiety having from two to six carbon atoms and one or more heteroatom from the group N, O, S (or oxidised versions thereof) which may be optionally benzofused at any available position. This includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, benzodioxole and the like. For the group NB2, which is heterocycloalkyl, the saturated heterocyclic moiety must contain at least one N atom. This includes, for example, azetidinyl, pyrrolidinyl, piperidinyl and the like.
The term xe2x80x9cheterocycloalkenylxe2x80x9d refers to an alicyclic moiety having from three to six carbon atoms and one or more heteroatoms from the group N, O, S and having in addition one double bond. This term includes, for example, dihydropyranyl.
The term xe2x80x9carylxe2x80x9d refers to an aromatic carbocyclic radical having a single ring or two condensed rings, optionally substituted with an aryl group substituent. This term includes, for example phenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic ring systems of five to ten atoms of which at least one atom is selected from O, N and S, and optionally substituted with an aryl group substituent. This term includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
The term xe2x80x9caryl group substituentxe2x80x9d refers to a substituent chosen from halogen, CN, CF3, CHF2, CH2F, OCF3, OCF2H, OCFH2 and NO2.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cbenzofusedxe2x80x9d refers to the addition of a benzene ring sharing a common bond with the defined ring system.
The term xe2x80x9ccycloimidylxe2x80x9d refers to a saturated ring of five to ten atoms containing the atom sequence xe2x80x94C(xe2x95x90O)NC(xe2x95x90O)xe2x80x94. The ring may be optionally benzofused at any available position. Examples include succinimidoyl, phthalimidoyl and hydantoinyl.
The term xe2x80x9coptionally substitutedxe2x80x9d means optionally substituted with one or more of the groups specified, at any available position or positions. The terms xe2x80x9cprotected aminoxe2x80x9d, xe2x80x9cprotected carboxyxe2x80x9d and xe2x80x9cprotected hydroxamic acidxe2x80x9d mean amino, carboxy and hydroxamic acid groups which can be protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or may be in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily-cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester. A hydroxamic acid may be protected as either N or O-substituted derivatives, such as O-benzyl or O-tert-butyldimethylsilyl.
Salts of compounds of formula (I) include pharmaceutically-acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
When the xe2x80x9cprotected carboxyxe2x80x9d group in compounds of the invention is an esterified carboxyl group, it may be a metabolically-labile ester of formula CO2R9 where R9 may be an ethyl, benzyl, phenethyl, phenylpropyl, xe2x80x9cxcex1 or xcex2-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl, 2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl, 2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl or pivaloylmethyl group.
Compounds of the general formula (I) may be prepared by any suitable method known in the art and/or by the following processes. It will be appreciated that, where a particular stereoisomer of formula (I) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material, and/or isomers can be resolved from mixtures using conventional separation techniques (e.g. HPLC).The compounds according to the invention may be prepared by the following process. In the description and formulae below the groups R1, R2 and B are as defined above, and Y is NHOH, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction sequence. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see Greene T. W. et al, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley Interscience (1999).
Thus, for example, compounds of the invention may be prepared by the following general route: 
Acids of formula (IV), where X is for example an alkoxy group, e.g. methoxy or ethoxy or a chiral auxiliary, e.g. R-4-benzyl-oxazolidin-2-one, may be prepared by deprotection of an ester of formula (VI) (where W is for example a tert-butyl or benzyl group) using, for example, an acid such as trifluoroacetic acid or by reaction with hydrogen in the presence of an appropriate catalyst such as palladium on carbon. Esters of formula (VI) may be prepared by reaction of an ester of formula (VII), wherein Z is an appropriate leaving group such as a halide, for example a bromide, or an alkyl or aryl sulfonate such as methanesulfonate, with an ester of formula (VIII). Suitable conditions for this reaction include the treatment of compound (VIII) with a strong organic base, such as n-butyllithium or sodium hexamethyldisilazide, in an inert solvent such as tetrahydrofuran at an appropriate temperature such as xe2x88x9278xc2x0 C. to 0xc2x0 C., followed by the slow addition of (VII).
Many esters of formulae (VII) and (VIII) or amines of formula (V) are known in the literature or may be prepared by standard methods known to those skilled in the art or by methods described in the examples hereinafter.
The acids of formula (IV) may be used to prepare compounds of formula (III) by reaction with an amine of formula B2NH (V) using standard methods known to those skilled in the art, for example, by in situ activation of an acid of formula (IV) using for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, advantageously in the presence of catalyst such as 4-dimethylaminopyridine, in a halogenated hydrocarbon, e.g. dichloromethane, followed by subsequent addition of an amine of formula (V). Alternatively, an acid of formula (IV) may be activated, for example by conversion to an acid halide such as an acid chloride by reaction with a halogenating agent such as oxalyl chloride, in the presence of a catalyst such as N,N-dimethylformamide in a halogenated hydrocarbon, e.g. dichloromethane. The acid chloride (which may or may not be isolated) can then be reacted with an amine of formula (V) in the presence of an amine base such as triethylamine in a halogenated hydrocarbon, e.g. dichloromethane.
Carboxylic acids of formula (II) may be prepared by deprotection of a suitably protected carboxylic acid of formula (III), where X is removed for example by lithium hydroxide in the case of an alkyl ester, e.g. ethyl or lithium hydroxide/hydrogen peroxide in the case of a chiral auxiliary such as R-4-benzyl-oxazolidin-2-one, using appropriate solvent and temperature conditions such as those described in the examples hereinafter.
The acids of formula (II) may be used to prepare compounds of formula (I) under conditions well known in the literature. For example, treatment of acids of formula (II) with oxalyl chloride in an inert solvent (such as dichloromethane) gives an intermediate acid chloride, which may or may not be isolated, but which in turn is reacted with hydroxylamine at a suitable temperature such as room temperature to give the desired hydroxamic acids (I). Alternatively, an acid of formula (II) maybe activated in situ using for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, advantageously in the presence of a catalyst such as a N-hydroxy compound, e.g. N-hydroxybenzotriazole, using suitable conditions, e.g. in N,N dimethylformamide at xe2x88x9210xc2x0 C., prior to the subsequent addition of a suitably protected hydroxylamine such as tert-butyldimethyl silyl hydroxylamine and maybe an an amine base such as N-methylmorpholine followed by warming to ambient temperature. The protecting group maybe removed using appropriate conditions, such as water or tetrabutylammonium fluoride and acetic acid in tetrahydrofuran at 0xc2x0 C., to yield the desired hydroxamic acids of formula (I).
Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I). Thus, for example, a compound of formula (I) wherein is a C1-6 alkyl group may be prepared by hydrogenation (using palladium on carbon in suitable solvent, such as an alcohol, e.g. ethanol) of a compound of formula (I) wherein R1 is a C2-6 alkenyl group.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
The compounds according to the invention exhibit in vitro inhibiting activities with respect to the stromelysin, collagenase, gelatinase, ADAM or ADAM-TS enzymes. Compounds according to the invention may also exhibit in vitro inhibition of membrane shedding events known to be mediated by metalloproteinases, for example, xcex1-APP, ACE, TGF-xcex1, TNF-xcex1, Fas ligand, selectins, TNFR-I, TNFR-II, CD30, I1-6R, CD43, CD44, CD16-I, CD16-II, Folate receptor, CD23, or IL-1RII.
The activity and selectivity of the compounds may be determined by use of the appropriate enzyme inhibition test, for example as described in Examples A-M of WO-A-9805635, by the assay for the inhibition of CD23 shedding described in WO-A-9924399 or by the assay of TNF RI shedding described in WO-A-0056704.
This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from disorders or diseases which can be attributed to metalloproteinases.
Accordingly, the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloproteinases such as found in certain metastatic tumour cell lines.
As mentioned above, compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of TNF and MMPs. Accordingly in another aspect, this invention concerns:
a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by TNF and/or MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, and
a compound of formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and
the use of a compound of formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMs.
The disease or conditions referred to above include inflammatory diseases, autoimmune diseases, cancer, cardiovascular diseases, diseases involving tissue breakdown. Appropriate diseases include rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer""s disease, stroke, vasculitis, Crohn""s disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis and those involving tissue breakdown such as bone resorption, haemorrhage, coagulation, acute phase response, cachexia and anorexia, acute infections, HIV infections, fever, shock states, graft versus host reactions, dermatological conditions, surgical wound healing, psoriasis, atopic dermatitis, epidermolysis bullosa, tumour growth, angiogenesis and invasion by secondary metastases, ophthalmological disease, retinopathy, corneal ulceration, reperfusion injury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endosclerosis, aspirin-independent anti-thrombosis, systemic lupus erythematosus and solid organ transplant.
Compounds of formula (I) may also be useful in the treatment of pelvic inflammatory disease (PID), age-related macular degeneration and cancer-induced bone resorption. Further, they can be used in the treatment of lung diseases, e.g. selected from cystic fibrosis, adult respiratory distress syndrome (ARDS), emphysema, bronchitis obliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolar damage, pulmonary Langerhan""s cell granulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronic obstructive pulmonary disease (COPD).
For the treatment of all disorders or diseases previously indicated, the compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc, the compounds of the invention are effective in the treatment of humans.
The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions oft he invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (I) are employed. For the purposes of this specification, topical application includes mouth washes and gargles.
Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the abovexe2x80x94indicated conditions (about 2.5 mg to about 7 g per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.